The cerebral cortex is the most evolved and expanded brain structure in humans that underlies our highest intellectual abilities. Stereotypic connections between neurons in the cortex define how information is processed in the cortex. For example, layer 5 pyramidal neurons from the motor and somatosensory cortex send axonal projections subcerebrally down to the spinal cord (corticospinal tract or CST), while layers 2/3 neurons send their axons across the midline to the contralateral hemisphere. Recent experiments have identified 3 key genes - Fezf2, Ctip2 and Satb2 - that regulate cortical neuron projection identities. Fezf2 and Ctip2 together regulate CST projections and Satb2 regulates callosal projections. Fezf2, Ctip2 and Satb2 also appear to regulate the expression of each other such that the final projection identity is the sum of all these genetic interactions. In this proposal, I will explore the genetic and molecular mechanisms by which these genes specify projection identity of cortical neurons. I also propose to understand the biochemistry of these processes, especially that of Satb2, which is a chromatin remodeling protein. By understanding how Satb2 alters chromatin structure to influence cell fate, we can get an insight into the epigenetic mechanism of cell fate specification in the cortex. Epigenetic control of fate determination is starting to emerge as a common theme during development, from differentiation of embryonic stem cells to specification of organ specific cell types. The overall goals of this proposal are to understand the fundamental mechanisms that set up the cortio-spinal tract and callosal circuitry in mammals. Problems in these how circuits underlie several psychiatric diseases such as schizophrenia, autism and ADHD. By understanding how these circuits are set up during development and identifying the molecules that are key to proper circuit development, we can begin to identify genes that could be targeted for therapy. RELEVANCE (See instructions): Callosal deficiency has been reported in severe psychiatric diseases such as schizophrenia, autism, Tourette's syndrome and attention deficit hyperactivity disorder (ADHD). A developmental abnormality in these circuits leads to several mental disorders, including microcephaly (Meckel-Grueber syndrome) and microlissencephaly, X-linked form of Kallmann syndrome. The overall goals of this research are to define the genetic and molecular pathways that specify cortical projections in order to understand how to repair broken circuits.